Cardiac infarction followed by ischemic injury is a major cause of death worldwide. Digitalis, the oldest and best characterized heart failure drug, protects against ischemia-reperfusion injury, and it does so through activation of the mitochondrial ATP-sensitive K+ channel (mitoKATp). The central hypothesis of this project is that ouabain-activated signals are relayed to mitochondria, resulting in mitoKATp opening, increased production of reactive oxygen species (ROS) and activation of survival kinases that protect the heart. Our long-term goal is to uncover the mechanisms that regulate digitalis-induced cardioprotection through activation of the Na,K-ATPase / mitoKATp pathway. During this period, we will focus on the mechanism of signal transmission from the sarcolemmal Na,K-ATPase to mitochondria.
Aim 1 will test the hypothesis that digitalis causes formation of functionally active caveolar microdomains (signalosomes) that interact with the mitochondrial outer membrane, leading to mitoKATp opening and inhibition of the mitochondrial permeability transition.
Aim 2 will investigate signalosome recycling and the persistence of signalosome function.
Aim 3 will investigate signalosome assembly and transport using electron microscopy and immunogold labeling.
Aim 4 will investigate key aspects of digitalis protection and signaling in the rabbit heart model, whose cardiac function and digitalis pharmacology are closer to those in human heart. A variety of experimental approaches will be used. Signalosomes will be purified from perfused hearts and tested for functional activity on mitochondria isolated from untreated hearts. Results of these physiological studies will be supported by parallel studies of infarct size on perfused hearts. Purified signalosomes will also be subjected to biochemical and structural analyses to characterize their composition and origin.
A major goal of this research is to discover how to reduce the damage to the heart that occurs after a heart attack. Digitalis, the oldest and best characterized drug for heart failure, protects against this damage, and this proposal seeks to understand how digitalis interacts with the cell to send this protective message to its specific mitochondrial target inside the cell. This understanding can lead to therapeutic interventions that will reduce a major cause of death.
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